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| Status |
Public on May 16, 2023 |
| Title |
Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). While CNS-resident glial cells and infiltrating immune cells contribute to MS pathogenesis, the networks that govern peripheral-central immune crosstalk and coordinate functionality among these ontologically distinct populations remain unclear. Here we show, in mice and humans, that astrocyte- and CD44hiCD4+ T cell-sourced interleukin-3 (IL-3) programs microglia and infiltrating myeloid cells to exacerbate neuroinflammation by inciting a cellular recruitment program that drives the accrual of immune cells in the CNS thereby worsening MS and its preclinical model experimental autoimmune encephalomyelitis (EAE). We find that CNS-resident astrocytes and peripherally-derived CD44hiCD4+ T cells generate IL-3 while resident microglia and infiltrating monocytes, macrophages, and dendritic cells respond to the cytokine by expressing IL-3Rɑ, IL-3's specific receptor. Astrocytic and T cell IL-3 elicit an immune migratory, recruitment, and chemotactic program by IL-3Rɑ+ myeloid cells that enhances immune cell infiltration into the CNS leading to exacerbated neuroinflammation, demyelination, and clinical disease. Multiregional single-nuclei RNA sequencing (snRNAseq) of human CNS tissue from unaffected controls and MS patients reveals the appearance of a subset of IL3RA-expressing myeloid cells in MS plaques with unique recruitment, migratory, and chemotactic programing and function. In humans with MS, IL3RA expression by plaque myeloid cells and IL-3 levels in the cerebrospinal fluid (CSF) predict myeloid and T cell abundance and recruitment into the CNS. Together, our findings establish IL-3:IL-3RA signaling as a bidirectional glial-peripheral immune crosstalk network that promotes neuroinflammation, prompts immune cell recruitment to the CNS, and worsens MS.
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| Overall design |
Description of samples and human subjects: Twelve fresh frozen brain tissue specimens, consisting of 6 MS cases (4 males and 2 females, age: 64±6) and 6 unaffected controls (4 males and 2 females, age: 63±3.3), were obtained through the NIH NeuroBiobank from the Human Brain and Spinal Fluid Resource Center, UCLA. All neuropsychological, diagnostic, and autopsy protocols were approved by the respective Institutional Review Boards. For the cases, each specimen contained a visible plaque and adjacent normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM). The unaffected control specimens consisted of NAWM and NAGM.
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| Contributor(s) |
Lee D, Fullard JF, Roussos P |
| Citation(s) |
37160117 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AG082185 |
The adaptive-innate immune interactome across multiple tissues in Alzheimer's disease |
MOUNT SINAI SCHOOL OF MEDICINE |
Vahram Haroutunian |
| R01 AG082185 |
The adaptive-innate immune interactome across multiple tissues in Alzheimer's disease |
MOUNT SINAI SCHOOL OF MEDICINE |
Donghoon Lee |
| R01 AG082185 |
The adaptive-innate immune interactome across multiple tissues in Alzheimer's disease |
MOUNT SINAI SCHOOL OF MEDICINE |
Cameron Stuart McAlpine |
| R01 AG082185 |
The adaptive-innate immune interactome across multiple tissues in Alzheimer's disease |
MOUNT SINAI SCHOOL OF MEDICINE |
Panagiotis Roussos |
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| Submission date |
Mar 20, 2023 |
| Last update date |
Feb 08, 2024 |
| Contact name |
Donghoon Lee |
| E-mail(s) |
donghoon.lee@mssm.edu
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| Organization name |
Icahn School of Medicine at Mount Sinai
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| Department |
Psychiatry, Genetics and Genomic Sciences
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| Street address |
1399 Park Ave
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (30)
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| GSM7108090 |
MS-5024, grey matter, snRNA-seq |
| GSM7108091 |
MS-5024, plaque, snRNA-seq |
| GSM7108092 |
MS-5024, white matter, snRNA-seq |
| GSM7108093 |
MS-5068, grey matter, snRNA-seq |
| GSM7108094 |
MS-5068, plaque, snRNA-seq |
| GSM7108095 |
MS-5068, white matter, snRNA-seq |
| GSM7108096 |
MS-5072, grey matter, snRNA-seq |
| GSM7108097 |
MS-5072, white matter, snRNA-seq |
| GSM7108098 |
MS-5086, grey matter, snRNA-seq |
| GSM7108099 |
MS-5086, white matter, snRNA-seq |
| GSM7108100 |
MS-5090, grey matter, snRNA-seq |
| GSM7108101 |
MS-5090, plaque, snRNA-seq |
| GSM7108102 |
MS-5090, white matter, snRNA-seq |
| GSM7108103 |
MS-5093, grey matter, snRNA-seq |
| GSM7108104 |
MS-5093, plaque, snRNA-seq |
| GSM7108105 |
MS-5093, white matter, snRNA-seq |
| GSM7108106 |
MS-5095, grey matter, snRNA-seq |
| GSM7108107 |
MS-5095, plaque, snRNA-seq |
| GSM7108108 |
MS-5095, white matter, snRNA-seq |
| GSM7108109 |
MS-5116, grey matter, snRNA-seq |
| GSM7108110 |
MS-5116, white matter, snRNA-seq |
| GSM7108111 |
MS-5144, grey matter, snRNA-seq |
| GSM7108112 |
MS-5144, white matter, snRNA-seq |
| GSM7108113 |
MS-5185, grey matter, snRNA-seq |
| GSM7108114 |
MS-5185, white matter, snRNA-seq |
| GSM7108115 |
MS-5190, grey matter, snRNA-seq |
| GSM7108116 |
MS-5190, white matter, snRNA-seq |
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| Relations |
| BioProject |
PRJNA946811 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE227781_220805_MS-snRNA-seq_manifest.csv.gz |
501 b |
(ftp)(http) |
CSV |
| GSE227781_RAW.tar |
309.0 Mb |
(http)(custom) |
TAR (of H5) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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